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The Role of Sartans in the Treatment of Stroke and Subarachnoid Hemorrhage: a Narrative Review of Preclinical and Clinical Studies

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The Role of Sartans in the Treatment of Stroke and Subarachnoid Hemorrhage: a Narrative Review of Preclinical and Clinical Studies brain sciences Review The Role of Sartans in the Treatment of Stroke and Subarachnoid Hemorrhage: A Narrative Review of Preclinical and Clinical Studies Stefan Wanderer 1,2,*, Basil E. Grüter 1,2 , Fabio Strange 1,2 , Sivani Sivanrupan 2 , Stefano Di Santo 3, Hans Rudolf Widmer 3 , Javier Fandino 1,2, Serge Marbacher 1,2 and Lukas Andereggen 1,2 1 Department of Neurosurgery, Kantonsspital Aarau, 5001 Aarau, Switzerland; [email protected] (B.E.G.); [email protected] (F.S.); [email protected] (J.F.); [email protected] (S.M.); [email protected] (L.A.) 2 Cerebrovascular Research Group, Neurosurgery, Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland; [email protected] 3 Department of Neurosurgery, Neurocenter and Regenerative Neuroscience Cluster, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; [email protected] (S.D.S.); [email protected] (H.R.W.) * Correspondence: [email protected] or [email protected]; Tel.: +41-628-384-141 Received: 17 January 2020; Accepted: 5 March 2020; Published: 7 March 2020 Abstract: Background: Delayed cerebral vasospasm (DCVS) due to aneurysmal subarachnoid hemorrhage (aSAH) and its sequela, delayed cerebral ischemia (DCI), are associated with poor functional outcome. Endothelin-1 (ET-1) is known to play a major role in mediating cerebral vasoconstriction. Angiotensin-II-type-1-receptor antagonists such as Sartans may have a beneficial effect after aSAH by reducing DCVS due to crosstalk with the endothelin system. In this review, we discuss the role of Sartans in the treatment of stroke and their potential impact in aSAH. Methods: We conducted a literature research of the MEDLINE PubMed database in accordance with PRISMA criteria on articles published between 1980 to 2019 reviewing: “Sartans AND ischemic stroke”. Of 227 studies, 64 preclinical and 19 clinical trials fulfilled the eligibility criteria. Results: There was a positive effect of Sartans on ischemic stroke in both preclinical and clinical settings (attenuating ischemic brain damage, reducing cerebral inflammation and infarct size, increasing cerebral blood flow). In addition, Sartans reduced DCVS after aSAH in animal models by diminishing the effect of ET-1 mediated vasoconstriction (including cerebral inflammation and cerebral epileptogenic activity reduction, cerebral blood flow autoregulation restoration as well as pressure-dependent cerebral vasoconstriction). Conclusion: Thus, Sartans might play a key role in the treatment of patients with aSAH. Keywords: aneurysmal subarachnoid hemorrhage; delayed cerebral vasospasm; ischemic stroke; Sartans; therapeutic interventions 1. Introduction Aneurysmal subarachnoid hemorrhage (aSAH) induces delayed cerebral vasospasm (DCVS) [1], cerebral inflammation [2,3], early brain injury [4], cortical spreading depression [5], delayed cerebral ischemia (DCI) [6], and lack of cerebral autoregulation [7] contributing to poor functional patients’ outcome. DCVS remains a major cause of patient’s morbidity and mortality by inducing delayed cerebral ischemia [8]. Brain Sci. 2020, 10, 153; doi:10.3390/brainsci10030153 www.mdpi.com/journal/brainsci Brain Sci. 2020, 10, 153 2 of 25 Multiple studies showed that endothelin-1 (ET-1), a most potent vasoconstrictor [9–11], plays a key role in the development of DCVS [12–19]. Although endothelin-A-receptor (ETA-R) antagonists in the treatment of DCVS in animal models are effective [10,20], clinical studies did not show beneficial effects [21,22]. It has been reported that the polypeptide angiotensin-II acts through two specific receptors, in essence the angiotensin-II-type-1- and angiotensin-II-type-2-receptor (AT2-1-R and AT2-2-R). Important to note is that activation of the AT2-1-R results in vasoconstriction while binding of angiotensin-II to the AT2-2-R causes vasorelaxation [23]. In line with this notion, preclinical as well as clinical trials showed promising results of Sartans, which are AT2-1-R antagonists, in ischemic stroke. Hence, Sartans may have a positive effect after aSAH by reducing DCVS due to crosstalk with the endothelin system. Thus, we aimed to analyze the potential role of Sartans in the treatment of aSAH. 2. Materials and Methods We conducted a systematic literature research of the MEDLINE PubMed database in accordance with PRISMA guidelines on preclinical studies on the one and on clinical studies on the other hand published between 1980 to 2019 reviewing: “Sartans and ischemic stroke” [24]. Only articles in English were chosen for review. Search items with “Sartans” (n = 19,064) and “ischemic stroke” (n = 89,465) were extracted. For “Sartans AND ischemic stroke”, 227 publications met the inclusion criteria by excluding studies with commentary only, any duplicates, or results not commenting on cerebral effects of Sartans. Two hundred and twenty-seven studies were assessed for eligibility, 83 met inclusion criteria for systematic review and qualitative analysis with 64 preclinical studies (Figure1 demonstrates the inclusion pathway for basic research studies selected via MEDLINE PubMed search) and 19 clinical studies (Figure2 shows the inclusion pathway for clinical research studies selected via MEDLINE PubMed search).Brain Sci. 2020, 10, x FOR PEER REVIEW 3 of 23 Figure 1. TwoFigure hundred 1. Two and hundred twenty-seven and twenty-seven articles articles (published (published 01-01-1980–01-07-2019) 01-01-1980–01-07-2019) were detected were detected for preclinical andfor clinical preclinical research and clinical articles. research After articles. manual After manual abstract abstract screening screening for for preclinical preclinical research research articles articles only, 79 articles remained for further analysis. Each of the 79 articles was explicitly screened only, 79 articlesfor remained potential drug for applications further analysis. after ischemic Each stroke. of theFinally, 79 64 articles articles waswere included explicitly for qualitative screened for potential drug applicationsanalysis. after ischemic stroke. Finally, 64 articles were included for qualitative analysis. Brain Sci. 2020, 10, 153 3 of 25 Brain Sci. 2020, 10, x FOR PEER REVIEW 4 of 23 FigureFigure 2. 2.Two Two hundred hundred and and twenty-seven twenty-seven articles articles (published (published 01-01-1980–01-07-2019) 01-01-1980–01-07-2019) were were detected detected for preclinicalfor preclinical and clinical and clinical research research articles. articles. After manualAfter manual abstract abstract screening screening for clinical for clinical research research articles only,articles 46 articlesonly, 46remained articles remained for further for further analysis. analysis. Each ofEach the of 46 the articles 46 articles was was explicitly explicitly screened screened for potentialfor potential drug applicationsdrug applications afterischemic after ischemic stroke. stroke. Finally, Finally, 19 articles 19 werearticles included were included for final analysis.for final analysis. Of the articles included in the final analysis, a systematic review on the beneficial and non-beneficial eff3.ect Results in the preclinical and clinical settings was performed. Summary measures are reported as outcome measures (i.e., infarct size, neurocognition, inflammation). 3.1. Preclinical Studies on Sartans in Animal Models of Ischemic Stroke 3. Results The search finally yielded 64 preclinical studies on “Sartans AND ischemic stroke”, eligible for 3.1.systematic Preclinical review Studies (Table on Sartans 1). in Animal Models of Ischemic Stroke The search finally yielded 64 preclinical studies on “Sartans AND ischemic stroke”, eligible for systematic review (Table1). Brain Sci. 2020, 10, 153 4 of 25 Table 1. Tabular listing of different preclinical studies showing various effects of Sartan administration (Abbreviations: Angiotensin-II-type-1-receptor (AT2-1-R); Angiotensin-II-type-2-receptor (AT2-2-R); common carotid artery occlusion (CCAO); chemokine receptor 2 (CCR2); cluster of differentiation (CD); candesartan (CS); desoxy ribonucleic acid (DNA); endothelial nitric oxide synthase (eNOS); endothelin-A-receptor (ETA-R); hours (h); inducible nitric oxide synthase (iNOS); irbesartan (IS); kilogram (kg); losartan (LS); middle cerebral artery occlusion (MCAO); matrix-metallo-proteinase (MMP); messenger ribonucleic acid (mRNA); milligram (mg); minutes (min); n-acetyl-glucosamine oligomer (NAGO); nlr family pyrin domain containing 3 (NLRP3); oxygen glucose deprivation (OGD); olmesartan (OMS); stroke-resistant spontaneously hypertensive rats (SR-SHR); telmisartan (TMS); tumor necrosis factor alpha (TNFα); ribonucleic acid (RNA); vascular endothelial growth factor (VEGF); valsartan (VS)). Drug Model Outcome Beneficial Effect Special Remarks TMS [25] Global ischemic mice model Cerebral perfusion Restored cerebral blood flow - Improved neuroscore and decreased infarct size, TMS [26] MCAO mice Neuroscore, infarct size increased cerebral blood flow, reduced superoxide - production and inflammatory cytokine expression Murine model of Reduced stroke volume 72 h after transient ischemia, Infarct size, No reduction in stroke volume 72 h TMS [27] transient and permanent likewise pro-inflammatory adhesion molecules and reperfusion injury after permanent ischemia focal ischemia infiltration of inflammatory cells in the ischemic region Attenuated ischemic brain damage, neurological deficits and superoxide production in ischemic area; Focal brain ischemia, TMS [28] MCAO mice attenuated reduction of
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